PROJECT SUMMARY This application proposes to address the critical need to include underrepresented populations in genomic research, with the purpose of enhancing our understanding of the genetic and phenotypic landscape of multiple sclerosis in the Hispanic population. Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease of the central nervous system affecting more than 400,000 individuals in the United States. MS is characterized by chronic inflammation, myelin loss, gliosis, and varying degrees of axonal pathology which impair saltatory conduction along axons that is necessary for normal functioning of nerve impulses. MS has an undetermined etiology and results in episodic or progressive neurological dysfunction. Although life span is modestly shortened, most patients experience increasing disability and consequent deterioration in quality of life. MS thus carries a significant morbidity that takes an immeasurable toll on the patients and their family members. The involvement of genetic factors in MS has long been appreciated. However, the clinical heterogeneity and complex etiology of MS have been confounding factors for genetic studies. While the first confirmed MS genetic association (with the HLA-DRB1*1501 allele) was identified in the early 1970's, further gene discoveries were limited until late 2007. At that time, we demonstrated that a common non-synonymous functional SNP in the IL7RA gene was associated with an increased risk of MS. This result was confirmed in the first genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC). These breakthroughs, along with both statistical and technological advances, have led to the identification and confirmed association of >190 genetic variants for MS susceptibility. Despite these advances, we have only uncovered a relatively small proportion of the genetic influences in MS. Much is yet to be understood regarding the role of these and other genes in MS. We must explore how these known genetic factors influence not only disease susceptibility, but disease outcomes, therapeutics, and responses to environmental exposures. While current research findings are unraveling the genetic underpinnings of individuals with Northern European genetic ancestry, large genetic studies of MS in Hispanics have yet to be realized. Moreover, the generalization of current findings to individuals of different genetic ancestry is a significant and unanswered question, especially in light of the reported differences in prevalence, clinical course, and progression of MS across various ancestral populations. We hypothesize that observed phenotypic differences between racial/ethnic populations are influenced by population-specific genetic factors. Our proposal seeks to broaden our understanding of the genetic etiology of multiple sclerosis, with a specific focus on performing the first battery of comprehensive analyses to elucidate the genetic and phenotypic manifestations of MS in the diverse Hispanic population, an understudied group that represents a rapidly growing percentage of the US population. To achieve this, we propose three specific aims: 1) Characterize established MS risk loci within a Hispanic patient cohort; 2) Perform genome-wide scans to identify novel genetic loci for MS susceptibility; 3) Explore genotype-phenotype correlations across racial/ethnic populations.